Cavernous nerve stimulation via unidirectional propagation of action potentials

ABSTRACT

Methods of using unidirectionally propagating action potentials (UPAPs) for cavernous nerve stimulation and for certain disorders are provided. Stimulators capable of creating such UPAPs include, but are not limited to, miniature implantable stimulators (i.e., microstimulators), possibly with programmably configurable electrodes. A method of stimulating a cavernous nerve includes providing at least one implantable stimulator with at least two cathodic electrodes; programming stimulation parameters for the cathodic electrodes to radially steer an electric field generated by the cathodic electrodes to apply stimulation that unidirectionally propagates action potentials along a cavernous nerve; and applying the stimulation to the cavernous nerve in accordance with the stimulation parameters to generate orthodromic action potentials traveling in one direction along the nerve, thereby limiting side effects of bidirectional stimulation.

This application is a divisional and claims the benefit of priorityunder 35 USC 120, of U.S. patent application Ser. No. 10/176,743, filedJun. 20, 2002, now U.S. Pat. No. 7,203,548. The disclosure of the priorapplication is considered part of, and is incorporated by referenceherein, the disclosure of this application.

FIELD OF THE INVENTION

The present invention generally relates to implantable medical systemsand methods, and more particularly relates to unidirectionallypropagating action potentials of the cavernous nerve and uses thereof.

BACKGROUND OF THE INVENTION

Implantable electrical stimulation devices have proven therapeutic in awide variety of diseases and disorders. Pacemakers and implantablecardiac defibrillators (ICDs) have proven highly effective in thetreatment of a number of cardiac conditions (e.g., arrhythmias). Spinalcord stimulation (SCS) systems have long been accepted as a therapeuticmodality for the treatment of chronic pain syndromes. Deep brainstimulation has also been applied therapeutically for well over a decadefor the treatment of refractory chronic pain syndromes, and it has alsorecently been applied in additional areas such as movement disorders. Inrecent investigations, peripheral nerve stimulation (PNS) systems havedemonstrated efficacy in the treatment of chronic pain syndromes, and anumber of additional applications are currently under investigation.Finally, functional electrical stimulation (FES) systems such as theFreehand™ system by NeuroControl™ Corporation of Cleveland, Ohio havebeen applied to restore some functionality to paralyzed extremities inspinal cord injury patients.

Current implantable electrical stimulation systems typically consist ofa system with electrodes on a lead, separate from but connected to animplantable pulse generator (IPG) that contains the power source and thestimulation circuitry. A number of these systems have multipleprogrammable electrodes, allowing each electrode to be configured as ananode, a cathode, or as an open circuit (i.e., electricallydisconnected). However, these types of leaded systems have severaldisadvantages. The implantation procedure may be rather difficult andtime-consuming, as the electrodes and the IPG must usually be implantedin separate areas and the lead must be tunneled through body tissue toconnect to the IPG. Also, the leads are typically thin and rather longand are thus prone to mechanical damage over time. Additionally, manyconventional systems typically consist of a relatively large IPG, whichcan have a negative cosmetic appearance if positioned subcutaneously.

Neurons typically propagate signals in one direction. Peripheral nervefibers that propagate signals away from the central nervous system (CNS,i.e., the brain and the spinal cord) and towards the periphery andviscera are referred to as efferent nerve fibers. Peripheral nervefibers that propagate signals away from the periphery and viscera andtowards the CNS are referred to as afferent nerve fibers.

Efferent impulses may initiate a variety of actions, from movement of amuscle to initiation of changes in the heart rate or force ofcontraction or in the level of constriction of the vascular smoothmuscle in arterioles. Through increasing or decreasing the activity ofefferent fibers, the CNS can, for example, alter the blood pressure bychanging the characteristics of the cardiovascular system.

Afferent impulses from specialized nerve endings or receptors inform thecontrolling neurons in the CNS about characteristics of the system,e.g., if a limb is feeling pain or if blood pressure is high or low.Most peripheral nerves contain both afferent and efferent nerve fibers.

A typical individual neuron consists of a soma (i.e., cell body), whichcontains the nucleus of the cell; dendrites, which receive input frompre-synaptic neurons; and an axon, which send signals via axon terminals(i.e., the distal portion of the axon) to post-synaptic neurons (or toeffector cells, e.g., muscle fibers). An action potential is initiatedat the initial segment of the axon (i.e., the proximal portion of theaxon) when triggered by input from the dendrites. An action potential isan electrochemical signal that propagates from the initial segment downthe axon to the axon terminals. Such propagation is referred to asorthodromic. (Orthodromic is defined as “of, relating to, or inducingnerve impulses along an axon in the normal direction.”) Action potentialpropagation in the opposite direction is referred to as antidromic.(Antidromic is defined as “proceeding or conducting in a directionopposite to the usual one—used especially of a nerve impulse or fiber.”)

In a neuron at rest, i.e., that is not propagating an action potential,the inside of the axon is negatively charged relative to the outside ofthe neuron, i.e., the membrane of the axon is at a negative restingpotential.

When the soma receives sufficient stimulation at its associateddendrites, it initiates an action potential at the initial segment,which travels orthodromically down the axon. An action potential isinitiated and propagated by opening channels in the axon membrane toallow positive charge (e.g., sodium ions) to enter the axon. This causesthe voltage of the inside of the axon to become positive, i.e., itdepolarizes a segment of the axon. Depolarization of one part of theaxon causes depolarization of an adjacent patch of axon; this mechanismallows a wave of depolarization to sweep down the axon. After a briefperiod of depolarization (e.g., approximately 1 msec), the axon membraneautomatically repolarizes to return to a resting state.

Electrical stimulation causes depolarization of the local axon membraneand may be used to initiate action potentials. For instance, electricalactivation of an axon performed near the middle of an axon (i.e., not atthe initial segment) produces two action potentials. One actionpotential propagates orthodromically, while the other propagatesantidromically.

SUMMARY OF THE INVENTION

The invention disclosed and claimed herein addresses problems notedabove and others by providing miniature implantable stimulators (i.e.,microstimulators) with programmably configurable electrodes. Inaddition, to further address the above and other problems, the inventiondisclosed and claimed herein provides miniature implantable stimulatorscapable of unidirectional propagation of action potentials (UPAPs).Further, the instant disclosure teaches and claims methods of usingUPAPs in certain locations and for certain disorders.

A microstimulator may be implanted via a small incision and/or viaendoscopic means. A more complicated surgical procedure may be requiredfor sufficient access to the nerve or portion of the nerve (e.g., nervefibers surrounded by scar tissue) or for purposes of fixing theneurostimulator in place. A single microstimulator may be implanted, ortwo or more microstimulators may be implanted to achieve greaterstimulation of the neural fibers.

The microstimulators used with the present invention possesses one ormore of the following properties, among others:

-   -   at least two electrodes (e.g., one active electrode and one        reference electrode) for applying stimulating current to        surrounding tissue;    -   electrical and/or mechanical components encapsulated in a        hermetic package made from biocompatible material(s);    -   an electrical coil or other means of receiving energy and/or        information inside the package, which receives power and/or data        by inductive or radio-frequency (RF) coupling to a transmitting        coil placed outside the body;    -   means for receiving and/or transmitting signals via telemetry;    -   means for receiving and/or storing electrical power within the        microstimulator; and    -   a form factor making the microstimulator implantable via a        minimal surgical procedure.

In some configurations, the microstimulator has at least threeelectrodes. In certain configurations, the microstimulator is leadless,while in others it may include electrodes on a relatively short lead.Additional microstimulator configurations are discussed in the detaileddescription of the invention.

Each electrode or section of a partitioned electrode may be configuredvia programming of stimulation parameters (i.e., programmablyconfigured) as a cathode, an anode, or an open circuit with differentcurrent outputs. This allows the microstimulator to be “electricallypositioned” once it has been implanted or otherwise fixed in place. Thisalso allows the stimulation electrodes to be redefined via reprogrammingof the stimulation parameters should the microstimulator migrateslightly. In turn, this allows stimulation to be directed to theappropriate site without needing to physically manipulate themicrostimulator. Additionally, the use of the proper set(s) ofelectrodes allows more localized and selective stimulation of the targetstructures and reduces the magnitude of the injected electric currentrequired to achieve neural stimulation, which results in less powerconsumed by the microstimulator.

A microstimulator may operate independently, or in a coordinated mannerwith other implanted devices, or with external devices. For instance, amicrostimulator may incorporate means for sensing a patient's condition,which it may then use to control stimulation parameters in a closed loopmanner. The sensing and stimulating means may be incorporated into asingle microstimulator, or a sensing means may communicate sensedinformation to at least one microstimulator with stimulating means.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects of the present invention will be moreapparent from the following more particular description thereof,presented in conjunction with the following drawings wherein:

FIG. 1A is a section view through an exemplary, two-electrodemicrostimulator that may be used with certain embodiments of the presentinvention;

FIG. 1B is an isometric view of an exemplary, two-electrodemicrostimulator that may be used with certain embodiments of the presentinvention;

FIG. 1C is an isometric view of an exemplary, two or more electrodemicrostimulator that may be used with certain embodiments of the presentinvention;

FIG. 2A is an isometric view of an exemplary microstimulator of thepresent invention, including a plurality of electrodes;

FIG. 2B is an isometric view of an exemplary microstimulator of thepresent invention, including one or more cuff electrodes;

FIG. 2C is a section view taken through 2C-2C of FIG. 2B;

FIG. 2D is a section view taken through 2D-2D of FIG. 2B;

FIG. 2E is an isometric view of an exemplary microstimulator of thepresent invention, including a plurality of partitioned electrodes;

FIGS. 3A and 3B show isometric views of microstimulators with fixationdevices;

FIG. 3C depicts a microstimulator with a fixation device that includeshelices that wrap around a nerve or other body tissue;

FIG. 4 illustrates possible external components of the invention;

FIG. 5 depicts a system of implantable devices that communicate witheach other and/or with external control/programming devices;

FIG. 6A illustrates various autonomic nerves in the head, neck, andthorax;

FIG. 6B is a cross-section through the neck, at the level of cervicalvertebra C7;

FIG. 6C illustrates various autonomic nerves in the abdomen;

FIG. 7A depicts the nerves of the male pelvic viscera and surroundinganatomy, where a stimulation system of the present invention may beimplanted; and

FIG. 7B is a section view through the body of a penis.

Corresponding reference characters indicate corresponding componentsthroughout the several views of the drawings.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best mode presently contemplated forcarrying out the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe determined with reference to the claims.

Unidirectionally Propagating Action Potentials (UPAPs)

As mentioned earlier, electrical activation of an axon usually producesaction potentials that propagate in both the orthodromic and antidromicdirections. Generation of a unidirectionally propagating actionpotential (UPAP) requires three essential components:

(1) Anodic Block in One Direction: Depolarization of an axon membraneleads to two action potentials traveling in opposite directions. Inorder to generate a UPAP, the propagation of one of the actionpotentials is blocked (i.e., arrested or inhibited), while the other isallowed to propagate. To block or arrest an action potential, a sectionof an axon membrane along the path of the undesired action potential iskept hyperpolarized during the time (or part of the time) the actionpotential would have traveled through that segment. To hyperpolarize themembrane, an electrode with anodic current is used. Therefore, to createa UPAP, the membrane must be depolarized at one electrode andhyperpolarized at another electrode. For instance, a cathodic currentdepolarizes the local axon membrane and initiates action potentials inopposing directions. A high anodic current may be used to hyperpolarizea section of axon membrane, thereby arresting action potentialpropagation in that direction.

Due to properties of the neurons, significantly less current is requiredto depolarize an axon enough to initiate an action potential than thecurrent that is required to hyperpolarize an axon enough to arrest anaction potential. Thus, the current that must be applied at the anode toarrest an action potential is typically higher in amplitude and oflonger duration than that required for neurostimulation. Since thecurrent flows between the cathode and the anode, this results in arelatively large cathodic current as well. This additional currentrequirement is not damaging to the cell or difficult to achieve.However, the generation of such high currents requires more energy fromthe neurostimulator and also requires electrodes with a relatively largesurface area, so as to maintain safe levels of charge density andcurrent density.

(2) Rebound Depolarization Control: Experimentally, if the very highanodic current used for hyperpolarization of the axon is discontinuedabruptly, then the portion of the axon that was hyperpolarized suddenlydepolarizes due to the non-linear properties of the axon membrane. Inother words, if the hyperpolarizing anodic pulse is suddenlydiscontinued, the axon membrane can undergo a rebound depolarization(also known as anodic break) which may result in the generation ofaction potentials. Thus, to avoid rebound depolarization, the anodiccurrent may be discontinued gradually, i.e., tapered off.

(3) Virtual Cathode Elimination: A nerve cuff is typically used forgeneration of UPAPs, as explained further presently. When a nerve cuffis used, it is desired that the current that flows between the anode andthe cathode stay within the nerve cuff. However, some of the currentinevitably flows from the anode, out of the nerve cuff, around theoutside of the nerve cuff, and back in the other end, to the cathode.Since the hyperpolarizing current must be relatively large in magnitude,this “leakage” current is relatively high in magnitude as well. As thisleakage current leaves the cuff at the end proximal to the anode, iteffectively behaves as a “virtual cathode.” (Under normal bi-directionalstimulation conditions, the virtual cathode current is relatively low inamplitude, so it may not create sufficient depolarization to fire anaction potential. Even if it does, with bi-directional stimulation theeffect is likely to be indistinguishable from stimulation at the actualcathode.) In this case, the virtual cathode current is relatively highin amplitude, and thus can initiate an action potential. This isunwelcome, since the purpose of the nearby anode is to hyperpolarize thenerve and prevent action potential propagation in the direction of theanode. Different techniques have been used to eliminate the virtualcathode effect, including the introduction of an additional anode at theother end of the nerve cuff, as described in more detail presently.

Anodic Block in One Direction

Generating a UPAP requires that an unwanted propagating action potentialbe arrested (in one direction). A nerve containing nerve fibers ofdiffering diameters and with differing conduction velocities may respondwell to stimulation when the site of action potential initiation andsite of arrest are closely spaced to minimize stimulus pulsewidth (andconsequent charge injection). Such an arrangement may take the form of aconventional bipolar electrode configuration in a nerve cuff with theanode located at one end of the nerve cuff and the cathode locatedcloser to the other end of the cuff.

Since the hyperpolarizing anodic current pulse is applied when theaction potential is expected to reach the anode (or before), it ishelpful if the spacing between the electrodes is known. Assuming a knownvelocity of action potential propagation in given nerve fibers, the timeat which an action potential arrives at the anode may thus be predicted.Precise timing of the anodic pulse is also aided by known spacingbetween the electrodes and the nerve. Minimizing the spacing between theelectrodes and the nerve reduces the current required for stimulation.In addition, fully enclosed cuffs concentrate the current near thenerve, reducing the amplitude of the required (cathodic and anodic)currents. In order to ensure that spacing is both controlled andminimized, a nerve cuff is typically used for UPAP; however, anyarrangement in which the electrodes are closely apposed to the nerve,which also allows stimulation with less current, may be used for UPAP.

Virtual Cathode Elimination

UPAPs have been demonstrated in several experimental systems. In 1979,van den Honert and Mortimer demonstrated that single, unidirectionallypropagated action potentials could be elicited in peripheral nerves byelectrical stimuli of short duration. (See Van den Honert C; Mortimer JT “Generation of unidirectionally propagated action potentials in aperipheral nerve by brief stimuli” Science 1979 Dec. 14;206(4424):1311-2.) They reduced the depolarizing effects of the virtualcathode using a tripolar electrode configuration; the center electrodewas the cathode, and the two outside electrodes were anodes. The secondanode created an additional electric field that opposed the flow ofcurrent from the first anode to the cathode through the path outside thecuff. Arresting (i.e., blocking or inhibiting) propagation of actionpotentials from both anodes was avoided by injecting a smaller currentthrough the “escape” end anode than through the “arrest” end anode. Thismethod required coordinated control of two stimulators. The stimulationpulse for UPAP was quasitrapezoidal in shape with a plateau pulsewidthof 350 μsec and an exponential trailing phase having a fall time of 350μsec. The plateau amplitude necessary for UPAPs was 5-6 mA.

Other Methods of Generation of UPAP

In 1986, Ungar, et al. described a system for generation of UPAPs via a“collision block” in a cat myelinated peripheral nerve. (See Ungar I J;Mortimer J T; Sweeney J D “Generation of unidirectionally propagatingaction potentials using a monopolar electrode cuff.” Annals ofBiomedical Engineering 1986; 14(5):437-50.) This system used a monopolarelectrode cuff with the conductor positioned closest to the “arrest” endof the cuff. A single cathode located at least 5 mm from the arrest endresulted in unidirectional propagation with minimal current and chargeinjection. The range of stimulus current values that producedunidirectional propagation increased with increases in longitudinalasymmetry of cathode placement over the range of asymmetries tested. Thestimulus current pulse that minimized charge injection wasquasitrapezoidal in shape with a plateau pulsewidth of approximately 350μsec and an exponential trailing phase having a fall time ofapproximately 600 μsec. These stimulation parameters were found to beindependent of cuff geometry. Arrest efficiency was not degraded using acuff of sufficient internal diameter to prevent nerve compression inchronic implantation. The critical current density within theextracellular space of the electrode cuff required to produce conductionfailure at the arrest end was estimated to be 0.47±0.08 mA/mm². Thenecessary total cuff length for effective unidirectional stimulation wasfrom 32-48 mm.

Also in 1986, Sweeney, at al. described a system for generation of UPAPsusing an asymmetric two-electrode cuff (ATEC). (See Sweeney J D;Mortimer J T “An asymmetric two electrode cuff for generation ofunidirectionally propagated action potentials” IEEE Transactions onBiomedical Engineering 1986 June; 33(6):541-9.) This configurationdiffers from a standard bipolar cuff electrode in that the anode isenclosed by an insulating sheath of larger diameter than the cathode andthe electrodes are asymmetrically placed within the cuff. The diameterof the cathode portion of the cuff was 16 mm and the diameter of theanode portion was as large as 26 mm. These electrodes were used toperform acute experiments in 13 adult cats. The stimulation pulse forUPAP was quasitrapezoidal in shape with a plateau pulsewidth of 200-500μsec and an exponential trailing phase having a fall time of 400-1200μsec. The plateau amplitude averaged 0.5 mA, and it varied from 0.1-2.3mA. From the related dimensions specified in the article, it seemslikely that the necessary total cuff length for effective unidirectionalstimulation was less than 3 cm.

In the above studies, only cuff electrodes were used. In addition, thepulse generators used in these studies were not implantable, and assuch, leads were used to enter the body and travel to the stimulationsite(s). Use of the implantable systems and methods disclosed hereinresults in improved generation and delivery of UPAPs, among otherimprovements that will be evident to those of skill in the art uponreview of the present disclosure.

The body reacts properly to orthodromic stimulation. Antidromicstimulation has a less significant physiological effect. UPAPs allow asystem to effectively select afferent or efferent stimulation. Forinstance, when stimulating a nerve, if an action potential is allowed toescape in the direction of signals traveling away from the viscera andperiphery and towards the CNS, both afferent and efferent fibers willtransport the action potentials, but only the afferent fibers (withsignals traveling orthodromically) will have an important physiologicaleffect. Antidromic pulses on the efferent fibers will have a lesssignificant physiological effect. This is referred to herein as“effective selection of afferent fibers.” Correspondingly, “effectiveselection of efferent fibers” is performed via stimulation with UPAPs inthe direction of signals traveling away from the CNS and toward theviscera and periphery, resulting in physiological effects viaorthodromic pulses on the efferent fibers, while the antidromic pulseson the afferent fibers have a less significant physiological effect.Several applications of neuromodulation would benefit fromneurostimulation applied to effectively select just the afferent or justthe efferent nerves. Systems and methods described herein provide thisability.

For example, the vagus nerve provides the primary parasympathetic nerveto the thoracic organs (e.g., the lungs and heart) and most of theabdominal organs (e.g., the stomach and small intestine). It originatesin the brainstem and runs in the neck through the carotid sheath withthe jugular vein and the common carotid artery, and then adjacent to theesophagus to the thoracic and abdominal viscera. Through stimulation toeffectively select afferent fibers (via UPAP stimulation traveling awayfrom the viscera and the periphery and towards the CNS), unidirectionalstimulation of the vagus nerve may be an effective treatment for avariety of disorders, including epilepsy and depression. Throughstimulation to effectively select efferent fibers (via UPAP stimulationtraveling away from the CNS and towards the viscera and the periphery),unidirectional stimulation of the vagus nerve may be an effectivetreatment for, e.g., tachycardia.

As yet another example, electrical stimulation of the cavernous nerve inthe pelvis has been demonstrated to produce and sustain erection, and assuch, is likely to prove an effective therapy for erectile dysfunction.The therapeutic effect is mediated by the efferent fibers, whichstimulate structures in the corpora cavernosa and spongiosum of thepenis. Stimulation of the afferent fibers of the cavernous nerve islikely to produce sensations that may be distracting, painful, or thelike. Effectively selecting the efferent fibers of the cavernousnerve(s) as a therapy for erectile dysfunction could allow relativelyhigher levels of stimulation, which might provide more effective therapyfor erectile dysfunction. This would also mitigate side effects such aspain at relatively high levels of stimulation.

The present invention provides, inter alia, microstimulator systems forstimulation of a nerve with unidirectionally propagating actionpotentials. In addition, the present invention provides programmablyconfigurable multielectrode microstimulator systems. The presentinvention also provides improved treatments for various medicalconditions, as mentioned above and described in more detail presently.

A microminiature implantable electrical stimulator, referred to hereinas a microstimulator, and known as the BION® microstimulator, has beendeveloped (by Advanced Bionics of Sylmar, Calif.) to overcome some ofthe disadvantages of traditional leaded systems. The standard BION is aleadless microstimulator, as the IPG and the electrodes have beencombined into a single microminiature package. A standard configurationof the BION is a cylinder that is about 3 mm in diameter and betweenabout 2 and 3 cm in length. This form factor allows the BION to beimplanted with relative ease and rapidity, e.g., via endoscopic orlaparoscopic techniques. With this configuration, the BION consists ofonly two electrodes: a reference, or indifferent, electrode at one endand an active electrode at the other end. In addition, with thisconfiguration, electrical signals delivered to nerves travel away fromthe stimulation location along the nerve fibers in both directions.

The microstimulators of the present invention may be similar to or ofthe type referred to as BION devices. The following documents describevarious features and details associated with the manufacture, operation,and use of BION implantable microstimulators, and are all incorporatedherein by reference:

Application/ Filing/ Patent/ Publication Publication No. Date Title U.S.Pat. No. Issued Implantable Microstimulator 5,193,539 Mar. 16, 1993 U.S.Pat. No. Issued Structure and Method of Manufacture 5,193,540 Mar. 16,1993 of an Implantable Microstimulator U.S. Pat. No. Issued ImplantableDevice Having an 5,312,439 May 17, 1994 Electrolytic Storage ElectrodeU.S. Pat. No. Issued Implantable Microstimulator 5,324,316 Jun. 28, 1994U.S. Pat. No. Issued Structure and Method of Manufacture 5,405,367 Apr.11, 1995 of an Implantable Microstimulator U.S. Pat. No. Issued ImprovedImplantable 6,051,017 Apr. 18, 2000 Microstimulator and SystemsEmploying Same PCT Publication Published Battery-Powered Patient WO98/37926 Sep. 3, 1998 Implantable Device PCT Publication PublishedSystem of Implantable Devices For WO 98/43700 Oct. 8, 1998 Monitoringand/or Affecting Body Parameters PCT Publication Published System ofImplantable Devices For WO 98/43701 Oct. 8, 1998 Monitoring and/orAffecting Body Parameters Published Micromodular Implants to ProvideSeptember, Electrical Stimulation of 1997 Paralyzed Muscles and Limbs,by Cameron, et al., published in IEEE Transactions on BiomedicalEngineering, Vol. 44, No. 9, pages 781-790.

As shown, for instance, in FIGS. 1A, 1B, and 1C, microstimulator device100 may include a narrow, elongated capsule 102 containing electricalcircuitry 104 connected to electrodes 110, which may pass through orcomprise a part of the walls of the capsule, as in FIG. 1A.Alternatively, electrodes 110 may be built into the capsule (FIG. 1B) orarranged along a lead(s) 112 (FIG. 1C), as described below. As detailedin the referenced patent publications, electrodes 110 generally comprisea stimulating electrode, or cathode (to be placed close to the targettissue) and an indifferent electrode, or anode (for completing thecircuit). Other configurations of microstimulator device 100 arepossible, as is evident from the above-referenced publications, and asdescribed in more detail herein.

Microstimulator 100 may be implanted via a minimal surgical procedure.Microstimulator 100 may be implanted with a surgical insertion toolspecifically designed for the purpose, or may be placed, for instance,via a small incision and through an insertion cannula. Alternatively,microstimulator 100 may be implanted via conventional surgical methods,or may be inserted using other endoscopic or laparoscopic techniques. Amore complicated surgical procedure may be required for sufficientaccess to a nerve or a portion of a nerve (e.g., nerve fibers surroundedby scar tissue, or more distal portions of the nerve) and/or for fixingthe neurostimulator in place.

The external surfaces of microstimulator 100 may advantageously becomposed of biocompatible materials. Capsule 102 may be made of, forinstance, glass, ceramic, or other material that provides a hermeticpackage that will exclude water vapor but permit passage ofelectromagnetic fields used to transmit data and/or power. Electrodes110 may be made of a noble or refractory metal or compound, such asplatinum, iridium, tantalum, titanium, titanium nitride, niobium, oralloys of any of these, in order to avoid corrosion, electrolysis, orother electrochemical reactions which could damage the surroundingtissues and the device.

Microstimulator 100 contains, when necessary and/or desired, electricalcircuitry 104 for receiving data and/or power from outside the body byinductive, radio-frequency (RF), or other electromagnetic coupling. Insome embodiments, electrical circuitry 104 includes an inductive coilfor receiving and transmitting RF data and/or power, an integratedcircuit (IC) chip(s) for decoding and storing stimulation parameters andgenerating stimulation pulses (either intermittent or continuous), andadditional discrete electrical components required to complete theelectrical circuit functions, e.g. capacitor(s), resistor(s), coil(s),diode(s), and the like.

Microstimulator 100 includes, when necessary and/or desired, aprogrammable memory 114 (which may be a part of the electrical circuitry104) for storing a set(s) of data, stimulation, and/or controlparameters. Among other things, memory 114 may allow stimulation andcontrol parameters to be adjusted to settings that are safe andefficacious with minimal discomfort for each individual. In addition,this allows the parameters to be adjusted to ensure that the stimulationfavors unidirectional propagation, when desired. The device(s) may beimplanted to deliver electrical stimulation to any location that islikely to be therapeutic, and the stimulation parameters may be adjustedto any set of parameters that prove efficacious, as described herein.Specific stimulation sites and parameters may provide therapeuticadvantages for various medical conditions, their forms, and/or severity.For instance, some patients may respond favorably to intermittentstimulation, while others may require continuous stimulation toalleviate their symptoms. Therefore, various embodiments of theinvention include means for providing stimulation intermittently and/orcontinuously.

The present invention provides means of maintaining the advantages ofearlier BION microstimulator systems while extending their functionalityto enable, inter alia, programmably configurable multielectrode systemsthat allow current to be more effectively directed towards a targetstimulation site. For instance, possible microstimulator configurationshave one or more programmably configurable electrodes 110 arranged alongthe stimulator outer capsule, as shown in FIG. 2A. Thus, amicrostimulator 100 may have a combination of programmably configurableand hard-wired electrodes, or may have only programmably configurableelectrodes, or may have only a plurality of hard-wired electrodes.

The configuration of microstimulator 100 may be determined by thestructure of the desired target, the surrounding area, and the method ofimplantation. The size and the shape of the microstimulator may bevaried in order to deliver more effective treatment. A thin, elongatedcylinder with electrodes at the ends and/or along the cylindrical caseare possible configurations, but other shapes, such as disks, spheres,helical structures, and others are possible. Additional alterations inconfiguration, such as the number, orientation, and shape of electrodes(which may be programmably configurable), may be varied in order todeliver more effective treatment. For instance, the electrodes may berectangular, semi-spherical, arcs, bands/rings, or any other usefulshape, and may be distributed along and/or around the surface of themicrostimulator.

Implantable microstimulator 100 is sufficiently small to permit itsplacement in or near the structures to be stimulated. For instance,capsule 102 may have a diameter of about 4-5 mm, or only about 3 mm, oreven less than 3 mm. Capsule 102 length may be about 25-40 mm, or onlyabout 20-25 mm, or even less than 20 mm. In some configurations and forsome stimulation sites, it may be useful for microstimulator 100 to belarger, to be of a different shape, or to include a lead(s) 112, asdescribed in more detail below.

In some embodiments of the instant invention, microstimulator 100comprises two or more leadless electrodes. However, one or moreelectrodes 110 may alternatively be located along short, flexible leads112 (FIG. 1C) as described in U.S. patent application Ser. No.09/624,130, filed Jul. 24, 2000, which is incorporated herein byreference in its entirety. The use of such leads permits, among otherthings, electrical stimulation to be directed more locally to targetedtissue(s) a short distance from the surgical fixation of the bulk of theimplantable microstimulator 100, while allowing most elements of themicrostimulator to be located in a more surgically convenient siteand/or in a position making telemetry with and/or powering and/orreplacing or removing the device simpler. This minimizes the distancetraversed and the surgical planes crossed by the device and any lead(s).Other uses of such configurations will be apparent presently. Forinstance, the electrodes may be positioned on a cuff(s) attached to themicrostimulator via a lead(s), as described below. In most uses of thisinvention, the leads are no longer than about 150 mm.

A microstimulator including a cuff electrode, as shown in FIGS. 2B, 2C,and 2D, may be a tripolar cuff electrode 116, possibly with anasymmetric placement of the center electrode. The electrodes maysubstantially form a ring, or the electrodes may be partitioned. Othercuff electrode configurations, as known to those of skill in the art,may alternatively or additionally be used. Such a cuff electrode may bea bipolar cuff electrode 118 with the anode placed farther from thenerve than the cathode via the use of an insulating sheath of largerdiameter for the anode than the cathode.

According to one embodiment of the invention, a microstimulator isattached to the cuff electrode via a lead 112. According to anotherembodiment of the invention, the cuff electrode is incorporated into themicrostimulator package, e.g., a microstimulator with a cuff electrodeattachment or other microstimulator fixation device 130, as in U.S.patent application Ser. No. 10/146,332 (the '332 application), whichapplication is incorporated herein by reference in its entirety. Asdiscussed in the '332 application, fixation device 130 may include oneor more electrodes 110. Examples of microstimulator cuff electrodeattachments/fixation devices 130 that may be used with the presentinvention are shown in, but not limited to, FIGS. 2B, 2C, 2D, 3A, 3B,and 3C.

In some applications, a microstimulator having a single cathode may besufficient. For instance, in some applications, such as pudendal nervestimulation for urge incontinence, the target may be rather large in atleast one dimension, allowing for some positioning error. However, forsome applications, a single cathode microstimulator may proveinsufficient or imperfect. For instance, if a target site is very smallin all dimensions, the microstimulator may be difficult to placeprecisely. For example, in deep brain stimulation for Parkinson'sdisease, the subthalamic nucleus has a maximum dimension of only 4-7 mm.Precisely placing the microstimulator at this target is likely to bedifficult, and even slight migration of the microstimulator over timemay reduce its efficacy. Other stimulation target sites may bephysically constrained, so that the microstimulator cannot be or isdifficult to position ideally in relation to the stimulation target. Forexample, the trigeminal ganglion, which receives sensation from all ofthe sensory nerves of the face, sits in a dural compartment known as thetrigeminal (Meckel's) cave, which lies in a depression on the anteriorslope of the petrous portion of the temporal bone. The trigeminal caveis a rather confined space that is surrounded by bone, and a soliddevice, even a microstimulator, may not be easy to manipulate andprecisely position in such a space.

In addition, in configurations where the microstimulator electrodes arecylindrical (either on a lead or on the case of a cylindricalmicrostimulator), the stimulation current is generally directed 360degrees radially outward. However, the target neurons may be locatedonly to one side of the electrode(s). Such a situation can result inhigher thresholds (due to wasted current directed away from the neuraltargets) as well as undesired stimulation of neurons that are not thedesired targets of stimulation. Solutions to this problem may involvelocating the electrodes to one side of the array. However, lead ormicrostimulator migration or rotation can make such designs ineffectiveor cumbersome to deploy and maintain.

The programmably configurable multielectrode microstimulators of thepresent invention, which can be “electrically positioned” as describedherein, address these and other problems. In certain embodiments, suchas shown in FIG. 2A, the microstimulator has a cylindrical shape, withelectrodes 110 configured as a plurality of anodes, cathodes, and/oropen circuit electrodes distributed along its surface. One or both endsmay be capped with an electrode 110, and one or more electrodes may bearranged along the microstimulator outer case.

In various embodiments, the end cap electrode(s) and/or those along thelength of the microstimulator and/or those on a lead attached to amicrostimulator can be further divided as shown in FIG. 2E into“partitioned” electrodes. Thus, individual electrodes, rather thanextending completely around the microstimulator, are partitioned intoshort arcs. In between each of the partitioned electrodes 110 is aninsulating material 120 to provide some electrical isolation. In anextreme alternative, the microstimulator could be covered with smallarcs of electrodes along its entire surface. The size of the electrodes110 and the insulating areas 120 may be uniform or may be independentand varied.

Electrodes configured along and/or around the microstimulator can beindividually programmed via stimulation parameters into variousconfigurations to “steer” the electric field radially around themicrostimulator (e.g., activating cathode(s) and anode(s) positionedsubstantially radially around the microstimulator) and/or longitudinallyalong the microstimulator (e.g., activating cathode(s) and anode(s)positioned substantially linearly along the microstimulator); such amicrostimulator can be “electrically positioned.” A relatively largenumber of small independent electrodes allows the electric field to beprogrammed in many configurations, such as very wide fields (e.g.,multiple grouped cathodes and anodes) or very narrow fields (e.g.,single electrodes for one cathode and one anode, using adjacentelectrodes). Such electrode array designs can mimic the electrode designof FIG. 1A, 1B, and/or 2A, for instance, while still allowing the morefocal stimulation from choosing individual electrodes.

Steering of the electric field (a.k.a., electrically positioning thestimulator) can be achieved by programming the stimulation parameters toactivate different electrodes and program each activated electrode as acathode, an anode, or an open circuit, as well as by controlling thecurrent flowing from each electrode that is activated. Such steeringcapability allows the electric field to be located more precisely totarget desired neurons, minimizing stimulation thresholds needed tocapture the desired neural targets, thus minimizing power consumption ofthe stimulator. Also, if microstimulator 100 or lead 112 happens torotate or migrate, some designs allow the electric field to bereprogrammed by adjusting the stimulation parameters, thus allowing themicrostimulator to be electrically positioned without having tophysically manipulate and reposition the microstimulator or electrodes.

All or some cathodes may be electrically connected, or some or all ofthe cathodes may be independently driven individually or in configurablegroups, i.e., the stimulator may have multiple stimulation channels.Similarly, all or some anodes may be electrically connected, or some orall of the anodes may be independently driven individually or inconfigurable groups. In some embodiments, at least one electrode is adedicated anode, and in various embodiments, at least one electrode is adedicated cathode.

In certain embodiments, microstimulator 100 is capable of producingwaveforms that can cause electrical stimulation and activation of neuralfibers. Such a waveform includes a periodic asymmetric square wave pulsethat consists of an initial cathodic pulse followed by a programmabledelay with minimal or no current and ending with an anodic chargerecovery pulse. Between stimulation pulses, the output of a givenelectrode consists of minimal and ideally no current. Other waveforms,including but not limited to trapezoidal and exponential, may be used.In some such nerve stimulation embodiments, the stimulator producespulses in the range from about 10 μA to about 15 mA, with a compliancevoltage from about 0.05 volts to about 20 volts, a pulsewidth range fromabout 10 μsec to about 4.0 msec, and a stimulation frequency range fromabout 1 pulse per second (pps) to about 10,000 pps.

Certain embodiments include means for producing a biphasic stimulationperiodic pulse waveform with a programmable stimulation phase pulsewidthin the range of about 50 μsec to about 5 msec and a charge recoveryphase having a programmable pulsewidth in the range of about 50 μsec toabout 5 msec. The biphasic stimulation periodic pulse waveform may besymmetric or asymmetric. The shapes of these waveforms may be any ofthose known to those of skill in the art. For example, the stimulationpulse may be a square pulse, and the charge recovery pulse may be asquare pulse, or it may be a trapezoidal or quasitrapezoidal pulse.

Some embodiments of the present invention, such as those producingUPAPs, include means for producing a stimulation pulse with, e.g., aquasitrapezoidal shape, with a programmable plateau pulsewidth in therange of about 10 μsec to about 5 msec, and a decaying trailing phase(e.g., an exponentially decaying trailing phase) having a programmablefall time in the range of about 50 μsec to about 5 msec. The stimulationpulse may be a square pulse, a trapezoidal or triangular pulse, or anyother shape known to those of skill in the art. The charge recoverypulse may be a square pulse, a trapezoidal or quasitrapezoidal pulse, orany other shape known to those of skill in the art, with, e.g., aplateau pulse width of about 50 μsec to about 10 msec. As describedearlier, this anodic charge recovery pulse may be tapered to avoidrebound depolarization and generation of additional action potentials.As such, the anodic pulse with, for instance, a trapezoidal orquasitrapezoidal pulse, may have a decaying trailing phase (e.g., anexponentially decaying trailing phase) with a programmable fall time inthe range of about 50 μsec to about 5 msec.

In some embodiments, part or all of the charge recovery pulse mayprecede the stimulation pulse. In certain embodiments, the chargerecovery pulse entirely precedes the stimulation pulse. In variousembodiments, a charge recovery pulse precedes the stimulation pulse andan additional charge recovery pulse follows the stimulation pulse.

If a tripolar or other multipolar electrode configuration is used (e.g.,a tripolar nerve cuff), then means for distributing the currentasymmetrically between the electrodes may be included, i.e., thepolarities and currents of the electrodes may be independentlyprogrammable. For example, in a nerve cuff with one cathode and twoanodes, the anodic currents may be independently programmed to be ofdifferent amplitudes.

The BION microstimulators described in the earlier referenced patentsand publications require some architectural modifications in order toprovide UPAP. The microstimulators 100 of the present inventionconfigured to provide UPAP include, in some embodiments, at least threeelectrodes 110, and more specifically, at least one cathode and at leasttwo anodes (which may be configured as such by the programmablestimulation parameters). The electrodes may be distributed collinearlyalong the long axis of the microstimulator, with the at least onecathode in between the at least two anodes. In some embodiments, theelectrodes surround the microstimulator radially. In alternativeembodiments, the electrodes may be segmented such that an individualelectrode extends part way around the microstimulator; this shouldprovide more focal application of cathodic and/or anodic currents.

In various embodiments, one or more of the electrodes may be a “virtual”electrode, for instance, when a microstimulator with a fixation devicesuch as a nerve cuff is used. A nerve cuff is typically used to maintainthe electrodes in close proximity to a specific target tissue and tomaintain a larger density of injected charge in the target area withinthe cuff. However, some of the current inevitably flows around theoutside the cuff. When this happens, the edges of the cuff behave as“virtual” electrodes. The virtual electrodes typically have a polarityopposite that of the “real” electrodes that create the current flowingaround the edge of the cuff. These virtual electrodes can stimulatetissue, as do real electrodes.

For example, a single real anode inside a nerve cuff with a referenceelectrode outside the cuff will behave similar to a tripolar cuffelectrode with real cathodes on either side of a real anode. As injectedelectric current from the anode flows towards the reference electrode(which is located external and typically relatively distant from thecuff), the current is forced to leave the cuff at the edges since thecuff is less electrically conducting than the tissue. As perceived bythe tissue inside the cuff, the edges of the cuff appear to behave assinks of current, thus creating virtual cathodes at the edges of thecuff. Similarly, if the single electrode in the cuff is a cathode, theedges of the cuff will behave as anodes.

The amount of current and current density that flows through the edgesof the cuff will determine the relative strength of the virtualelectrodes. Different means can be used to control the relative strengthof the virtual electrodes. For instance, by placing a single electrodeasymmetrically within the cuff and a reference electrode symmetricallyoutside the cuff, a stronger virtual electrode (more current) willtypically be created on the edge of the cuff that is closer to the realelectrode. As another example, by placing the reference electrodeasymmetrically outside the cuff and the real electrode symmetricallywithin the cuff, a stronger virtual electrode (more current) will becreated on the edge of the cuff that is closer to the referenceelectrode. As yet another example, by increasing the diameter of oneside of the cuff, the virtual electrode on that side can be maderelatively weaker. Similarly, by decreasing the diameter of one side ofthe cuff, the virtual electrode on that side can be made relativelystronger. These and other means to control the relative strength ofvirtual electrodes can be combined to allow for further control of therelative strength of the virtual electrodes.

As described above, due to the presence of virtual electrodes, systemswith a given number of real electrodes can behave like systems with agreater number of electrodes. For instance, a system with a single realelectrode, such as a single real cathode placed asymmetrically within anerve cuff or a single real cathode placed asymmetrically on amicrostimulator with a fixation device, can be used to generate UPAPs.The edge of the cuff/fixation device closer to the real electrode willbe a stronger virtual anode than the edge of the cuff/fixation devicefurther from the real electrode. Therefore, propagation of actionpotentials created by the cathode can be arrested by the strongervirtual anode but allowed to propagate past the weaker virtual anode.Previously described methods for controlling the relative strength ofthe virtual anodes can also be used in single real electrode UPAPgenerating systems. For purposes of this description and the claimsdefining the scope of the invention, virtual and real electrodes areboth encompassed by the term “electrodes”. Therefore, for instance, thissingle real electrode UPAP generating system comprises at least threeelectrodes: the “real” cathode and two “virtual” anodes. Similarly,where herein reference is made to “a cathode” or “an anode” the cathodeand/or anode may be “real” or “virtual”.

UPAPs can also be produced with systems containing only two realelectrodes. For instance, the asymmetric two-electrode cuff (ATEC)system described earlier used a larger cuff diameter at the anode sideof the cuff and asymmetrically placed the anode and cathode within thecuff. This configuration reduced the relative strength of the virtualcathode, thereby reducing the depolarizing effects of the virtualcathode. Similarly, a microstimulator with a fixation device, even onewith only two electrodes, can be configured to produce UPAPs. Inconfigurations where the anode and cathode share a power source, thecurrent that depolarizes the nerve at the cathode hyperpolarizes thenerve fibers at the anode. In configurations including, e.g., areference electrode, an anode, a cathode, and more than one powersource, the hyperpolarizing current may be, for instance, of longerduration and/or higher in amplitude than the depolarizing current. Theseanodes and cathodes may be real or virtual. Methods described above forreducing the relative strength of a virtual cathode can also be used inUPAP systems with two real electrodes.

Virtual electrodes can also be used to reduce the effect of othervirtual electrodes. A virtual cathode may be eliminated with theaddition of an anode on the opposite side of the cuff from the virtualcathode. This extra anode can also be a virtual anode. Additionally oralternatively, the virtual cathode can be addressed with the methodsdescribed above for controlling the relative strength of virtualelectrodes. For instance, in a two “real” electrode cuff system, avirtual cathode appears on the edge of the cuff near the real anode,while a virtual anode appears on the side near the real cathode. Byplacing the real electrodes asymmetrically within the cuff, in such away that the real anode is further from the edge of the cuff than thereal cathode, the relative strength of the virtual anode will increaseand the relative strength of the virtual cathode will diminish. Thissystem with two real electrodes will effectively produce UPAPs in thedirection of the real cathode, while arresting propagation in thedirection of the real anode.

As mentioned earlier, a microstimulator may include or be attached to afixation device that holds the microstimulator and/or electrodes inclose apposition to the nerve. Among other things, this may help controlthe spacing desired between the electrodes and target nerve. Forexample, the microstimulator might include or be integrated as part of anerve cuff. Various embodiments of this invention include a cuffelectrode assembly that allows UPAPs. Such a device may be a tripolarcuff electrode 116 (FIG. 2B), possibly with an asymmetric placement ofthe center (cathodic) electrode. Other cuff electrodes can be asdescribed above, where one or more of the electrodes is a virtualelectrode. According to some embodiments of the invention, amicrostimulator as in the '332 application, with examples shown in FIGS.3A-3C, includes a fixation device 130. Once again, one or more of theelectrodes may be a virtual electrode. According to other embodiments, amicrostimulator is attached to one or more cuff electrodes via a lead,as in FIG. 2B.

The microstimulator may also include means for simultaneously providinganodic current of different amplitude through two or more differentanodes. For example, when a microstimulator with a nerve cuff or thelike is used, this allows one anode to be used to produce a relativelyhigh amplitude hyperpolarizing anodic current, while another anode maybe used to produce a relatively low amplitude anodic current to shuntsome of the current that leaks outside the nerve cuff, therebypreventing depolarization and stimulation by a virtual cathode. In somesuch embodiments, the means includes two different current sources witha common cathode and different anodes. In some embodiments, the meansincludes programmable stimulation parameters. In some embodiments, themeans includes two or more microstimulators.

The present invention also provides means for unidirectional propagationof action potentials in a selected subset(s) of neurons by takingadvantage of the fact that the speed of an action potential depends onthe diameter of a neuron. For instance, as is known in the art, therelatively large diameter A-α fibers (up to about 22 micron diameter)conduct action potentials at up to about 120 m/sec, while the relativelysmall diameter C fibers (up to about 1 micron diameter) conduct actionpotentials at up to about 2 m/sec. As used herein, large diameter fibersmeans relatively large diameter nerve fibers, and includes A-α, A-β, andA-γ fibers, while small diameter fibers means relatively small diameternerve fibers, and includes A-δ, B, and C fibers. Through appropriatetiming, an action potential may be passed along one size fiber and maybe arrested in another.

For example, action potentials in large diameter afferent fibers travelrelatively faster than in small diameter afferent fibers. A relativelyhigh-amplitude depolarizing current is applied to the nerve to initiatebi-directional action potentials in both small and large diameter nervefibers. To arrest afferent propagation of action potentials in smalldiameter fibers, relatively high-amplitude hyperpolarizing anodiccurrent is applied at the anode after the large diameter actionpotentials has passed (or has at least been initiated) and before theaction potentials in the small diameter fibers has been initiated (or atleast before it has passed). Thus, some or all of the action potentialsin the small diameter afferent fibers would be arrested. To do thiswould likely require the electrodes to be spaced relatively far apart,for instance, with one or more microstimulators or with electrodes onleads attached to a microstimulator(s).

Similarly, action potentials in large diameter efferent fibers travelrelatively faster than in small diameter efferent fibers. Again, arelatively high-amplitude depolarizing current is applied to the nerveto initiate bi-directional action potentials in both small and largediameter nerve fibers. To arrest efferent propagation of actionpotentials in small diameter fibers, once again, relativelyhigh-amplitude hyperpolarizing anodic current is applied at the anodeafter the large diameter action potentials has passed (or has at leastbeen initiated) and before the action potentials in the small diameterfibers has been initiated (or at least before it has passed). Thus, someor all of the action potentials in the small diameter efferent fiberswould be arrested. As above, electrodes spaced relatively far apart,such as electrodes on leads attached to one or more microstimulators,would likely be required.

In another example, the present invention provides means for arrestingpropagation of action potentials in small and large diameter fibers inone direction along a nerve. As in the examples above, a relativelyhigh-amplitude depolarizing current is applied to the nerve to initiatebi-directional action potentials in both small and large diameter nervefibers. As used herein, a relatively high-amplitude depolarizing currentis applied at an amplitude of about 0.01 mA to about 15 mA, with a pulsewidth of about 0.01 msec to about 5.0 msec. To arrest propagation ofaction potentials in small and large diameter fibers, a hyperpolarizinganodic current(s), which is of relatively high-amplitude, is applied atthe anode before the action potentials in the small and large diametersfibers has passed. As used herein, relatively high-amplitudehyperpolarizing anodic current is applied at an amplitude of about 0.1mA to about 15 mA, with a pulse width of about 0.1 msec to about 10.0msec. In this and the examples above, the anodic current may be taperedat the end in order to reduce the likelihood of a rebound stimulation ofan action potential, as described earlier. Apply additional anodiccurrent(s) as needed to prevent stimulation at a virtual cathode.

As yet another example, the present invention provides means forarresting propagation of action potentials in large diameter fibers. Arelatively large cathodic current can initiate a bi-directional actionpotential in both small diameter and large diameter fibers. However, arelatively low-amplitude hyperpolarizing anodic current is more likelyto hyperpolarize a large diameter fiber than a small diameter fiber andis thus more likely to cause anodic block and arrest of action potentialpropagation in a large fiber. Thus, in order to selectively arrestaction potentials in large diameter fibers while allowing propagation ofaction potentials in small diameter fibers, the following steps may befollowed:

-   -   1) Apply a relatively high-amplitude depolarizing cathodic        current to the nerve. This will depolarize axons of all sizes        and will thus initiate bi-directional action potentials in both        small and large nerve fibers.    -   2) On the side(s) of the cathode on which arrest is desired,        apply a relatively low-amplitude hyperpolarizing anodic current        to the nerve. As used herein, relatively low-amplitude        hyperpolarizing anodic current is applied at an amplitude of        about 0.01 mA to about 10 mA, with a pulse width of about 0.01        msec to about 5.0 msec. This current should be sufficient to        hyperpolarize and arrest action potentials in large fibers but        not in small fibers, as large fibers are more easily        hyperpolarized than small fibers. Once again, the anodic current        may be tapered at the end to reduce the likelihood of rebound        stimulation.    -   3) Apply additional anodic current(s) simultaneously with the        steps above as needed to prevent stimulation at a virtual        cathode.

Stimulation parameters may have different effects on different neuraltissue, and parameters may be chosen to target specific neuralpopulations and to exclude others, or to increase neural activity inspecific neural populations and to decrease neural activity in others.As an example, relatively low frequency stimulation (i.e., less thanabout 50-100 Hz) typically has an excitatory effect on surroundingneural tissue, leading to increased neural activity, whereas relativelyhigh frequency stimulation (i.e., greater than about 50-100 Hz) may havean inhibitory effect, leading to decreased neural activity. Therefore,low frequency electrical stimulation may be used to increase electricalactivity of a nerve by increasing the number of action potentials persecond in either one direction or in both directions. As yet anotherexample, a relatively low-amplitude stimulation current is more likelyto initiate an action potential in large diameter fibers, while arelatively high-amplitude stimulation current is more likely to initiatean action potential in both large and small diameter fibers.

Some embodiments of implantable microstimulator 100 include a powersource and/or power storage device 126. Possible power options for amicrostimulator of the present invention include, but are not limitedto, an external power source coupled to the stimulation device, e.g.,via an RF link, a self-contained power source utilizing any suitablemeans of generation or storage of energy (e.g., a primary battery, areplenishable or rechargeable battery such as a lithium ion battery, anelectrolytic capacitor, a super- or ultra-capacitor, or the like), andif the self-contained power source is replenishable or rechargeable,means of replenishing or recharging the power source (e.g., an RF link,an optical link, a thermal link, or other energy-coupling link).

According to certain embodiments of the invention, a microstimulatoroperates independently. According to various embodiments of theinvention, a microstimulator operates in a coordinated manner with othermicrostimulator(s), other implanted device(s), or other device(s)external to the patient's body. For instance, a microstimulator maycontrol or operate under the control of another implantedmicrostimulator(s), other implanted device(s), or other device(s)external to the patient's body. A microstimulator may communicate withother implanted microstimulators, other implanted devices, and/ordevices external to a patient's body via, e.g., an RF link, anultrasonic link, a thermal link, an optical link, or the like.Specifically, a microstimulator may communicate with an external remotecontrol (e.g., patient and/or physician programmer) that is capable ofsending commands and/or data to a microstimulator and that may also becapable of receiving commands and/or data from a microstimulator.

In certain embodiments, and as illustrated in FIG. 4, the patient 170switches microstimulator 100 on and off by use of controller 180, whichmay be hand held. Microstimulator 100 is operated by controller 180 byany of various means, including sensing the proximity of a permanentmagnet located in controller 180, sensing RF transmissions fromcontroller 180, or the like.

External components for programming and/or providing power to variousembodiments of microstimulator 100 are also illustrated in FIG. 4. Whencommunication with microstimulator 100 is desired, patient 170 ispositioned on or near external communications appliance 190, whichappliance contains one or more inductive coils 192 or other means ofcommunication (e.g., RF transmitter and receiver). Externalcommunications appliance 190 is connected to or is a part of externalprogrammer 200 which may receive power 202 from a conventional powersource. External programmer 200 contains manual input means 208, e.g., akeypad, whereby the patient 170 or a caregiver 212 can request changesin the stimulation parameters produced during the normal operation ofmicrostimulator 100. In these embodiments, manual input means 208includes various electromechanical switches and/or visual displaydevices or the like that provide the patient and/or caregiver withinformation about the status and prior programming of microstimulator100.

Alternatively or additionally, external programmer 200 is provided withan interface means 216 for interacting with other computing means 218,such as by a serial interface cable or infrared link to a personalcomputer or to a telephone modem or the like. Such interface means 216may permit a clinician to monitor the status of the implant andprescribe new stimulation parameters from a remote location.

The external appliance(s) may be embedded in a cushion, pillow, mattresscover, or garment. Other possibilities exist, including a belt, scarf,patch, or other structure(s) that may be affixed to the patient's bodyor clothing. External appliances may include a package that can be,e.g., worn on the belt, may include an extension to a transmission coilaffixed, e.g., with a VELCRO band or adhesive, or may be combinations ofthese or other structures able to perform the functions describedherein.

In order to help determine the strength and/or duration of electricalstimulation required to produce the desired effect, in some embodiments,a patient's response to and/or need for treatment is sensed. Forexample, muscle activity (e.g., limb EMG), electrical activity of anerve (e.g., ENG), and/or electrical activity of the brain (e.g., EEG)may be sensed. Other measures of the state of the patient mayadditionally or alternatively be sensed. For instance, medication,neurotransmitter, hormone, interleukin, cytokine, lymphokine, chemokine,growth factor, and/or enzyme levels or their changes, and/or levels orchanges in other substance(s) borne in the blood and/or in thecerebrospinal fluid (CSF) may be sensed, using, e.g., one or moreChemically Sensitive Field-Effect Transistors (CHEMFETs) such asEnzyme-Selective Field-Effect Transistors (ENFETs) or Ion-SensitiveField-Effect Transistors (ISFETs, as are available from Sentron CMT ofEnschede, The Netherlands). For instance, the level or changes in levelof neuron-specific enolase, a key glycolytic enzyme, in either or boththe blood serum or CSF may be sensed. As another example, to senseerectile dysfunction, a penile tumescence sensor, penile arteriolepressure sensor, and/or nitric oxide sensor may be used.

As another example, when electrodes of implantable stimulator 100 areimplanted on or near the vagus nerve, a sensor or stimulating electrode(or other electrode) of microstimulator 100 may be used to sense changesin EEG resulting from the stimulation applied to the nerve.Alternatively, a “microstimulator” dedicated to sensory processescommunicates with a microstimulator that provides the stimulationpulses. The implant circuitry 104 may, if necessary, amplify andtransmit these sensed signals, which may be analog or digital. Othermethods of determining the required stimulation include sensingimpedance, pressure, acceleration, mechanical stress, and capacitance,as well as other methods mentioned herein, and yet others that will beevident to those of skill in the art upon review of the presentdisclosure. The sensed information may be used to control stimulationparameters in a closed-loop manner.

As mentioned earlier, use of, for instance, a multi-electrode cuff,where electrodes are present on the inner surface of the cuff, may beused to create UPAPs. In this example of sensing a physical condition ofa patient, sense amplifiers may be employed to sense the propagatingaction potentials that result from the cathodic stimulus from the cuff'sstimulating electrode. For instance, a technique (such as describedherein) to implement the UPAP is employed, and the signal at each end ofthe cuff, or at a more remote location(s) on the nerve, is measured. Ifthe UPAP generation is successful, then an action potential will besensed traveling only in the desired direction, for instance, at onlyone end of the cuff.

If the UPAP technique is unsuccessful, it may be because (1) no actionpotential was generated by the stimulus, (2) bi-directional actionpotentials were generated, (3) a UPAP was generated in the wrongdirection. In the case of such a failure, an algorithm can be employedto generate the correct UPAP. For instance, if no action potentials wereproduced, the cathodic stimulus may be increased until bi-directionalaction potentials are generated. If bi-directional action potentialswere produced or a UPAP was generated in the wrong direction, one of thetechniques discussed herein for creating UPAPs may be implemented andadjusted until the UPAP in the appropriate direction results. When usingvirtual and real electrodes, the configuration and/or stimulus strengthsmay be adjusted to create the effect. Or, if stimulus waveformcharacteristics are employed (trapezoidal pulses with an exponentialtrailing edge), the parameters of the waveforms may be adjusted untilthe proper UPAPs are generated.

In some instances, the time(s) of arrival of the sensed actionpotentials and/or evoked potentials at the electrodes may be used toadjust the UPAP-generating mechanisms. Since various nerve fiber typeshave different conduction velocities, the arrival time of an actionpotential (as defined by a waveform morphological feature, such as anupstroke, maximum rate of change of sensed amplitude, peak value, zerocrossing, or the like) at an electrode some distance from thestimulation site may be used to determine if the UPAP generation wassuccessful, i.e., whether the fiber type to be inhibited is no longergenerating action potentials in the direction to be blocked.

In certain instances, the morphology of the sensed action potentialsand/or evoked potentials may be used to determine the effectiveness ofUPAP generation. At an electrode close to the stimulating electrode, thedifference in propagation velocity between fibers is often not greatenough to create differences in arrival times between sensed propagatingaction potentials; that is, the sensed signal at a nearby electrode willbe a spatial- and time-averaged waveform that is made up of thetraveling action potentials of different fiber types. Techniques fordecomposing the waveform into the constituent action potentials from thedifferent fiber types have been proposed. (See, for instance, Barker, etal., “Determination of the Distribution of Conduction Velocities inHuman Nerve Trunks” Biomedical Engineering 26(2):76-81,1979 andSchoonhoven, et al., “The Inverse Problem in Electroneurography-I:Conceptual Basis and Mathematical Formulation” Biomedical Engineering35(10):769-777, 1988.) An algorithm incorporating waveform analysis canbe utilized to decompose the sensed signal to determine if the UPAP issuccessfully arresting the propagation of an action potential from aspecific fiber type(s).

As an example, the sensed waveform may be characterized during acalibration routine. A sensed signal may be obtained from the desiredUPAP configuration/parameters and compared to a sensed signal obtainedfrom bi-directional propagation configuration/parameters. The state ofbi-directional versus unidirectional propagation may be verified byeither or both sensed signals and/or by clinical symptoms. Thedifferences in the unidirectional and bi-directional waveforms could becharacterized by a feature or suite of features indicating thedifferences.

For instance, if it is reliably determined that the peak value of thesensed action potential from a fiber is related to the square of theconduction velocity of that fiber, then, given a known or assumeddistribution of fibers within the cuff electrode, the fibers which arepropagating action potentials may be inferred from the amplitude of thecompound action potential (CAP) waveshape. As an example, if largerfibers (which have higher conduction velocities) are to be blocked byUPAP techniques, then, during bidirectional propagation (e.g., forcalibration), large sensed CAP waveforms would be detected on theelectrode in the direction to be blocked. When the UPAP technique issuccessful, a dramatic reduction in sensed signal amplitude will result,due to blocked propagation of the larger fibers. There may still be apropagated CAP of lower amplitude sensed by the electrode due to somesmaller fibers being activated by the cathodic stimulus, but a sensethreshold can be established, where signals that exceed this thresholdindicate propagation by larger fibers and failure of the UPAP method.

In an alternative example, if sense electrodes are placed at each end ofa nerve cuff, a differential comparison can be made. After timing andgain adjustments are made, a large difference in signal amplitudebetween the two electrodes would indicate UPAP success, where a smalldifference in signals would indicate either loss of nerve capture orbilateral propagation.

Again, the stimulator may sense a physical condition of a patient bymonitoring the sensed signal(s) for the characteristic feature(s) todetermine if the UPAP generation was successful. If the UPAP succeeded,no changes need be made to the stimulator parameters or configuration.If the UPAP failed, stimulator parameter(s) and/or configuration may bemodified until the desired UPAP is recreated, as indicated by thesensed, characteristic waveform that indicates the UPAP. This system maybe periodically recalibrated, either automatically or during follow-upsessions with a clinician.

While a microstimulator may also incorporate means of sensing one ormore conditions of the patient, it may alternatively or additionally bedesirable to use a separate or specialized implantable device to senseand telemeter physiological conditions/responses in order to adjuststimulation parameters. This information may be transmitted to anexternal device, such as external appliance 190, or may be transmitteddirectly to implanted stimulator(s) 100. However, in some cases, it maynot be necessary or desired to include a sensing function or device, inwhich case stimulation parameters are fixed and/or determined andrefined, for instance, by patient feedback, or the like.

Thus, it is seen that in accordance with the present invention, one ormore external appliances may be provided to interact withmicrostimulator 100, and may be used to accomplish, potentially amongother things, one or more of the following functions:

-   -   Function 1: If necessary, transmit electrical power from        external programmer 200 via appliance 190 to microstimulator 100        in order to power the device and/or recharge power        source/storage device 126. External programmer 200 may include        an algorithm that adjusts stimulation parameters automatically        whenever microstimulator(s) 100 is/are recharged, whenever        communication is established between them, and/or when        instructed to do so.    -   Function 2: Transmit data from external programmer 200 via        external appliance 190 to implantable stimulator 100 in order to        change the operational parameters (e.g., electrical stimulation        parameters) used by stimulator 100.    -   Function 3: Transmit sensed data indicating a need for treatment        or in response to stimulation from neurostimulator 100 (e.g.,        EEG, change in neurotransmitter or medication level, or other        activity) to external programmer 200 via external appliance 190.    -   Function 4: Transmit data indicating state, address and/or type        of implantable stimulator 100 (e.g., battery level, stimulation        settings, etc.) to external programmer 200 via external        appliance 190.

For the treatment of various types and degrees of medical conditions, itmay be desirable to modify or adjust the algorithmic functions performedby the implanted and/or external components, as well as the surgicalapproaches, in ways that would be obvious to skilled practitioners ofthese arts. For example, in some situations, it may be desirable toemploy more than one implantable stimulator 100, each of which could beseparately controlled by means of a digital address. Multiple channelsand/or multiple patterns of stimulation might thereby be programmed bythe clinician and controlled by the patient in order to, for instance,stimulate larger areas of neural tissue in order to maximize therapeuticefficacy.

In some embodiments discussed earlier, microstimulator 100, or a groupof two or more microstimulators, is controlled via closed-loopoperation. A need for and/or response to stimulation is sensed viamicrostimulator 100, or by an additional microstimulator (which may ormay not be dedicated to the sensing function), or by another implantedor external device. If necessary, the sensed information is transmittedto microstimulator 100. In some embodiments, the stimulation parametersused by microstimulator 100 are automatically adjusted based on thesensed information. Thus, the stimulation parameters are adjusted in aclosed-loop manner to provide stimulation tailored to the need forand/or response to stimulation.

For instance, in some embodiments of the present invention, a first andsecond “stimulator” are provided. The second “stimulator” periodically(e.g. once per minute) records e.g., nerve activity (or medication,etc.), which it transmits to the first stimulator. The first stimulatoruses the sensed information to adjust stimulation parameters accordingto an algorithm programmed, e.g., by a clinician. For example,stimulation may be activated (or stimulation current amplitude may beincreased) in response to EEG changes indicative of an impending or anactual seizure. As another example, when the microstimulator is used tostimulate the cavernous nerve to produce an erection, stimulationcurrent amplitude may be increased in response to a decrease inintracavernosal pressure. Alternatively, one “microstimulator” performsboth the sensing and stimulating functions.

For example, as shown in the example of FIG. 5, a first microstimulator100, implanted beneath the skin of patient 170, provides electricalstimulation via electrodes 110 to a first location; a secondmicrostimulator 100′ provides electrical stimulation to a secondlocation; and a third microstimulator 100″ provides electricalstimulation to a third location. As mentioned earlier, the implanteddevices may operate independently or may operate in a coordinated mannerwith other similar implanted devices, other implanted devices, or otherdevices external to the patient's body, as shown by the control lines222, 223 and 224 in FIG. 5. That is, in accordance with certainembodiments of the invention, external controller 220 controls theoperation of each of the implanted microstimulators 100, 100′ and 100″.According to various embodiments of the invention, an implanted device,e.g. microstimulator 100, may control or operate under the control ofanother implanted device(s), e.g., microstimulator 100′ and/ormicrostimulator 100″. That is, a device made in accordance with theinvention may communicate with other implanted stimulators, otherimplanted devices, and/or devices external to a patient's body, e.g.,via an RF link, an ultrasonic link, a thermal link, an optical link, orother communications link. Specifically, as illustrated in FIG. 5,microstimulator 100, 100′, and/or 100″, made in accordance with theinvention, may communicate with an external remote control (e.g.,patient and/or physician programmer 220) that is capable of sendingcommands and/or data to implanted devices and that may also be capableof receiving commands and/or data from implanted devices.

For instance, two or more stimulators may be used in a UPAP system. Onestimulator may depolarize the nerve, inducing bi-directional propagationof action potentials. One or more additional stimulators may beresponsible for hyperpolarizing the nerve, or certain fiber types withinthe nerve. The stimulators may communicate with each other to coordinatethese activities, or they may communicate with and/or receivecommunications from an external controller. The stimulation parametersand/or timing may be fixed, adjusted manually, and/or automaticallyupdated based on sensed physical condition(s) of the patient. One ormore microstimulators included in the system may include a fixationdevice, such as a nerve cuff. For instance, in certain embodiments, thestimulator(s) used for hyperpolarizing include a nerve cuff, while thestimulator(s) for depolarizing do not.

A microstimulator made in accordance with the invention may incorporate,in some embodiments, first sensing means 228 for sensing therapeuticeffects, clinical variables, or other indicators of the state of thepatient, such as EEG, ENG, and/or EMG. The stimulator additionally oralternatively incorporates second means 229 for sensing levels orchanges in one or more medications, neurotransmitters, hormones,interleukins, cytokines, lymphokines, chemokines, growth factors,enzymes, and/or other substances in the blood plasma, in thecerebrospinal fluid, or in the local interstitial fluid. The stimulatoradditionally or alternatively incorporates third means 230 for sensingelectrical current levels and/or waveforms. Sensed information may beused to control the parameters of the stimulator(s) in a closed loopmanner, as shown by control lines 225, 226, and 227. Thus, the sensingmeans may be incorporated into a device that also includes electricalstimulation means, or the sensing means (that may or may not havestimulating means) may communicate the sensed information to anotherdevice(s) with stimulating means, or to another device capable ofcommanding other devices to stimulate. For instance, a “central” devicecan analyze the sensed data and command other devices to stimulateappropriately. This central device may or may not be implanted.

As described earlier, the present invention teaches a microstimulatorsystem for stimulation of a nerve with unidirectionally propagatingaction potentials that may effectively select the efferent fibers or theafferent fibers propagating more towards the periphery and viscera ormore towards the CNS. Such selective stimulation may be an effectivetreatment for a variety of disorders. For instance, and as discussed inmore detail below, stimulation of the vagus nerve with unidirectionallypropagating action potentials that effectively select and stimulate thetherapeutic afferent fibers of the vagus nerve may be an effectivetreatment for a variety of disorders, including epilepsy and/ordepression.

A commercially available vagus nerve stimulation (VNS) system iscurrently used as a therapy for refractory epilepsy. Epilepsy afflictsone to two percent of the population in the developed world, and anestimated 25-33% of these are refractory to medication and conventionalsurgery. The currently available VNS system produces a significantnumber of side effects due to recruitment of efferent fibers.

The vagus nerve 250 (see FIGS. 6A, 6B, and 6C) provides the primaryparasympathetic nerve to the thoracic organs and most of the abdominalorgans. It originates in the brainstem and runs in the neck through thecarotid sheath 252 (FIG. 6B) with jugular vein 256 and common carotidartery 258, and then adjacent to the esophagus to the thoracic andabdominal viscera. As seen in FIGS. 6A and 6C, vagus nerve 250 has manybranches, including pharyngeal and laryngeal branches 260, cardiacbranches 264, gastric branches 266, and pancreaticoduodenal branches268. Because the vagus nerve innervates the pharynx, the most commonside effect associated with VNS therapy is a hoarse voice duringstimulation. Some patients also experience a mild cough, tickling in theback of the pharynx, or increased hoarseness. Stimulation of the vagusnerve may also lead to a decreased opening of the vocal cords, whichresults in shortness of breath during exertion.

The vagus nerve provides parasympathetic innervation to the heart, andstimulation of the vagus nerve has been demonstrated to causebradycardia and arrhythmias. Stimulation of the left vagus nerve distalto the cardiac branch of the vagus nerve has not resulted insignificantly increased cardiac side effects; however, the stimulatingelectrodes may only be safely placed on this distal portion of the leftvagus nerve. Bilateral stimulation is not allowed, as stimulation of theright vagus nerve produces significant cardiac side effects. Finally,the vagus nerve provides parasympathetic innervation to the lungs andmost of the abdominal organs (e.g., the stomach and small intestine),and improper stimulation of the vagus nerve may impair properfunctioning of these organs.

Some embodiments of this invention include a microstimulator thatgenerates UPAPs of the vagus nerve (which, as used herein, includesbranches of the vagus nerve). A microstimulator may be implanted on ornear the vagus nerve in the neck region, e.g., by dissecting down to thecarotid sheath. A microstimulator may also/instead be surgicallyimplanted on or near a more proximal or distal portion of the vagusnerve. Various stimulator configurations may be used. For instance, acuff electrode, which may be part of a microstimulator, attached to amicrostimulator via a short lead, or attached to an IPG, may beimplanted around the vagus nerve.

A single microstimulator may be implanted, or two or moremicrostimulators may be implanted to achieve greater stimulation of thevagus nerve. According to some embodiments of the invention, a singlemicrostimulator is implanted for stimulation of the left vagus nerve.According to various embodiments of the invention, one microstimulatoris implanted for stimulation of the left vagus nerve and another isimplanted for stimulation of the right vagus nerve. Bilateralstimulation may be effected with two separate microstimulators or by amicrostimulator with multiple leads. Vagus nerve stimulation with UPAPsmay alternatively or additionally be provided by one or more IPGsattached to one or more leads with, for instance, electrodes in a nervecuff.

For instance, a UPAP system (e.g., a microstimulator with a fixationdevice, a nerve cuff attached to an IPG implanted in a subclavicularlocation, or the like) may be provided on the vagus nerve in the carotidsheath (unilaterally or bilaterally). Stimulation parameters maycomprise, for instance, a stimulation pulse with a quasitrapezoidalshape, with a plateau pulse width in the range of about 10 μsec to about5 msec and/or an exponentially decaying trailing phase having a falltime in the range of about 50 μsec to about 5 msec. A charge recoverypulse, may comprise, for instance, a quasitrapezoidal shape with aplateau pulsewidth of about 50 μsec to about 10 msec and/or a decayingtrailing phase with a fall time of about 50 μsec to about 5 msec. Otherpossible UPAP parameters are taught herein. In some electrodeconfigurations, for instance tripolar or other multipolarconfigurations, means for distributing the current asymmetricallybetween the electrodes may be included, i.e., the polarities andcurrents of the electrodes are independently programmable.

According to such an embodiment of the invention, the stimulation canincrease excitement of afferent fibers of the vagus nerve(s), therebytreating epilepsy and/or depression, while limiting side effectstypically caused by bidirectional stimulation that activates efferentfibers with orthodromically propagating action potentials. Low-frequencyelectrical stimulation (i.e., less than about 50-100 Hz) is likely toproduce the therapeutic activation. To determine the need for and/orresponse to such treatment, EEG of the cortex, thalamus, a regionadjacent to a scarred region of the brain, or any area of the brainknown to give rise to a seizure in a particular patient, may be sensed.Alternatively or additionally, limb EMG and/or other conditions, asknown to those of skill in the art, may be sensed.

Additional uses include the application to tachycardia via effectiveselection and stimulation of the efferent fibers of the vagus nerve,such as one or more superior and/or inferior cardiac branches.Electrodes capable of UPAP may be provided on the right and/or leftvagus nerve(s) in, for instance, the neck, the thorax, and/or adjacentto the esophagus. Excitatory stimulation (i.e., less than about 50-100Hz) should be used to stimulate vagal parasympathetic activity to theheart to promote a decrease in heart rate and thereby treat tachycardia.To determine the need for and/or response to such treatment, ECG, heartrate, blood pressure, blood flow, cardiac output, acceleration, and/orbreathing, for instance, may be sensed.

As another example, stimulation of the cavernous nerve(s) withunidirectionally propagating action potentials that effectively selectthe therapeutic parasympathetic efferent fibers of the cavernousnerve(s) may be an effective treatment for erectile dysfunction and mayminimize distracting, unpleasant, or uncomfortable sensation that may beassociated with electrical stimulation of the cavernous nerve(s).

Recent estimates suggest that the number of men in the U.S. witherectile dysfunction may be 10-20 million, and inclusion of men withpartial erectile dysfunction increases the estimate to about 30 million.Erectile dysfunction has a number of causes, both physiological andpsychological, and in many patients the disorder is multifactorial. Thecauses include several that are essentially neurologic in origin. Damageto the autonomic pathways innervating the penis may eliminate“psychogenic” erection initiated by the central nervous system. Lesionsof the somatic nervous pathways may impair reflexogenic erections andmay interrupt tactile sensation needed to maintain psychogenicerections. Spinal cord lesions may produce varying degrees of erectilefailure depending on the location and completeness of the lesions. Notonly do traumatic lesions affect erectile ability, but disorders leadingto peripheral neuropathy may impair neuronal innervation of the penis orof the sensory afferents.

A well-publicized medication is available for erectile dysfunction, butit requires an hour to exert its full effects, and it may havesignificant side effects such as abnormal vision, flushing, headache,and diarrhea. Intracavernosal injection therapy, in which a patientinjects vasodilator substances (e.g., papaverine) into the corpora ofthe penis, suffers a high rate of patient dropout, as do vacuumconstriction devices. Several forms of penile prostheses are available,including semirigid, malleable, and inflatable, but these havesignificant problems with mechanical failure, infection, and erosions.

The male erectile response is a vascular event initiated by neuronalaction and maintained by a complex interplay between vascular andneurological events. The pelvic splanchnic nerve plexus 280, the nervefibers of which originate in the sacral spinal cord (S2, S3, S4,respectively) and intertwine with the inferior hypogastric plexus 284,provides the primary parasympathetic input to the penis, i.e., thecorpus cavernosa 286 and the corpus spongiosum 288, via the greatercavernous nerve 290 and lesser cavernous nerve 292. This parasympatheticinput allows erection by relaxation of the smooth muscle and dilation ofthe helicine arteries of the penis. The cavernous nerves 290, 292 passbilaterally near the apex, mid, and base of prostate 294 and then nearthe posterolateral urethra (not shown). The nerves then run underneaththe pubic symphysis 296 and into the penis. Conversely, sympatheticinnervation from the hypogastric nerves, specifically from the inferiorhypogastric plexus 284, makes the penis flaccid due to constriction ofthe smooth muscle and helicine arteries of the penis.

One or more stimulators may be implanted to stimulate cavernous nerve(s)290, 292, branches thereof, and/or nerves that give rise to a cavernousnerve(s) (collectively referred to herein simply as cavernous nerves) inany of the aforementioned regions by dissecting down to the nerve(s).Such dissection may usually be performed through any incision allowingaccess to the prostate and/or the posterolateral urethra. For example,an incision could be made above the pubic symphysis 296, and the tissuesbetween the incision and at least one of the cavernous nerves could bedissected away. Alternatively, an incision may be made immediately belowthe pubic symphysis 296, or an incision may be made through theperineum. As another alternative, an incision may be made in thedorsolateral penis 298.

Some embodiments of this invention include a stimulator that allowsUPAPs of the cavernous nerve(s). Such a stimulator (for instance, amicrostimulator of the present invention) allows the effective selectionof efferent fibers. Via stimulation of primarily efferent fibers,unidirectional stimulation of the cavernous nerve(s) may be an effectivetreatment for erectile dysfunction. By effectively avoiding theproduction of orthodromic action potentials on the afferent fibers, suchstimulation may minimize distracting, unpleasant, or uncomfortablesensation that may be associated with electrical stimulation of thecavernous nerve(s) or other associated nerve fibers, as mentioned above.

According to such an embodiment of the invention, a UPAP system (e.g., amicrostimulator with a fixation device or a nerve cuff attached to anIPG implanted in the abdomen or the like) may be provided on one or morecavernous nerves or neurovascular bundles containing a cavernous nerve.Stimulation parameters may comprise, for instance, a stimulation pulsewith a quasitrapezoidal shape, with a plateau pulse width in the rangeof about 10 μsec to about 5 msec and an exponentially decaying trailingphase having a fall time in the range of about 50 μsec to about 5 msec.A charge recovery pulse, may comprise, for instance, a quasitrapezoidalshape with a plateau pulsewidth of about 50 μsec to about 10 msec and adecaying trailing phase with a fall time of about 50 μsec to about 5msec. Again, other possible UPAP parameters are taught herein. In someelectrode configurations, for instance, tripolar or other multipolarconfigurations, means for distributing the current asymmetricallybetween the electrodes may be included, i.e., the polarities andcurrents of the electrodes are independently programmable.

The stimulation can increase excitement of a nerve(s), such as acavernous nerve(s), thereby treating erectile dysfunction. Low-frequencyelectrical stimulation (i.e., less than about 50-100 Hz) is likely toproduce such activation. To determine the need for and/or response tosuch treatment, a penile tumescence sensor, penile arteriole pressuresensor, and/or nitric oxide sensor, for instance, may be used.

A single microstimulator may be implanted, or two or more systems may beimplanted to achieve greater stimulation of a cavernous nerve(s).According to one embodiment of the invention, a single microstimulatoris implanted for stimulation of a single cavernous nerve. According toanother embodiment of the invention, one microstimulator is implantedfor stimulation of one of the left cavernous nerves and another isimplanted for stimulation of one of the right cavernous nerves.According to other embodiments, several microstimulators are used: onefor each nerve to be stimulated, or even multiple for each nerve to bestimulated. Bilateral stimulation and other multiple stimulation sitetreatments may be effected with two separate microstimulators or by amicrostimulator with multiple leads. Cavernous nerve stimulation withUPAPs may alternatively or additionally be provided by one or more IPGsattached to one or more leads with, for instance, electrodes in a nervecuff.

Additionally, sensing means described earlier may be used to orchestratefirst the activation of microstimulator(s)/electrode(s) targeting onearea of a nerve, and then, when appropriate, themicrostimulator(s)/electrode(s) targeting the same or another area ofthe nerve, in order to, for instance, implement UPAPs. Alternatively,this orchestration may be programmed, and not based on a sensedcondition.

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the scope of the invention set forth in the claims.

1. Method of stimulating a cavernous nerve, the method comprising:providing at least one implantable microstimulator comprising a capsule,a power source capable of generating energy, disposed in the capsule andconfigured and arranged to power the implantable microstimulator, and atleast two cathodic electrodes and one anodic electrode forming a portionof a wall of the capsule; programming stimulation parameters for thecathodic electrodes to radially steer an electric field generated by thecathodic electrodes to apply stimulation that unidirectionallypropagates action potentials along a cavernous nerve; and applying thestimulation to the cavernous nerve in accordance with the stimulationparameters to generate orthodromic action potentials traveling in onedirection along the nerve, thereby limiting side effects ofbidirectional stimulation.
 2. The method of claim 1 wherein applying thestimulation to the cavernous nerve comprises applying the stimulation toefferent fibers, thereby treating erectile dysfunction while limitingside effects of bidirectional stimulation.
 3. The method of claim 1wherein the at least one microstimulator comprises a programmablyconfigurable microstimulator.
 4. The method of claim 1 wherein thecavernous nerve comprises at least one cavernous nerve, including theleft cavernous nerves, the right cavernous nerves, branches of the leftcavernous nerves, branches of the right cavernous nerves, nerves thatgive rise to at least one cavernous nerve, and neurovascular bundlescontaining at least one cavernous nerve.
 5. The method of claim 1wherein the method further comprises: applying a depolarizing cathodiccurrent to a nerve via at least one of the cathodic electrodes, whichthe cathodic current is sufficient to initiate bidirectional actionpotentials in large diameter nerve fibers and small diameter nervefibers; applying a hyperpolarizing anodic current to the nerve via theanodic electrode at a side of the microstimulator where arrest of theaction potentials is desired; and tapering the anodic current.
 6. Themethod of claim 5 further comprising applying the hyperpolarizing anodiccurrent before the action potentials pass the anodic electrode, whichhyperpolarizing anodic current is a relatively high-amplitudehyperpolarizing current, which high-amplitude hyperpolarizing current issufficient to arrest action potentials in large diameter nerve fibersand small diameter nerve fibers.
 7. The method of claim 5 furthercomprising waiting an amount of time allowing the action potentials topropagate in the large diameter nerve fibers, then applying thehyperpolarizing anodic current to the nerve at the side of themicrostimulator where arrest of the action potentials in the smalldiameter nerve fibers is desired, which hyperpolarizing current arrestsaction potentials in the small diameter nerve fibers.
 8. The method ofclaim 5 further comprising applying the hyperpolarizing anodic currentbefore the action potentials pass the anodic electrode, whichhyperpolarizing anodic current is a relatively low-amplitudehyperpolarizing current, which low-amplitude hyperpolarizing current issufficient to arrest action potentials in large diameter nerve fibersand allows propagation of action potentials in small diameter nervefibers.
 9. The method of claim 1, wherein applying the stimulation tothe cavernous nerve in accordance with the stimulation parameters togenerate orthodromic action potentials traveling in one direction alongthe nerve comprises applying the stimulation to the cavernous nerve at afirst position using at least one of the cathodic electrodes; applying ahyperpolarizing anodic current to the cavernous nerve at a secondposition using the anodic electrode; detecting a physiological conditioncharacteristic of propagation of an action potential generated inresponse to the depolarization of the cavernous nerve past the secondposition; and reprogramming the stimulation parameters used by theimplanted microstimulator to hyperpolarize the cavernous nerve.
 10. Themethod of claim 9, wherein the microstimulator further comprises asecond anodic electrode and wherein reprogramming the stimulationparameters to hyperpolarize the cavernous nerve comprises selecting thesecond anodic electrode to hyperpolarize the cavernous nerve.
 11. Themethod of claim 9, wherein detecting the physiological conditioncomprises detecting the action potential at a position past the secondposition.
 12. The method of claim 11, wherein detecting the actionpotential comprises detecting the action potential in relatively smalldiameter fibers of the cavernous nerve.
 13. The method of claim 9,further comprising implanting the microstimulator using a minimalsurgical procedure.
 14. The method of claim 1, wherein applying thestimulation to the cavernous nerve in accordance with the stimulationparameters to generate orthodromic action potentials traveling in onedirection along the nerve comprises stimulating the cavernous nerve byselecting a subset of a collection of electrodes positioned at differentlocations along a short axis of the microstimulator to direct electricalstimulation applied by the microstimulator to a position along thecavernous nerve, the collection of electrodes comprising the at leasttwo cathodic electrodes and the anodic electrode and the selecting beingdone in accordance with the stimulation parameters; and in response to aperceived reduction of stimulation of the cavernous nerve, transmittingto the microstimulator data indicating that at least some of thestimulation parameters are to change.
 15. The method of claim 14,further comprising stimulating the cavernous nerve by redirecting theelectrical stimulation applied by the microstimulator by steering theelectrical stimulation among at least the subset of the collection ofelectrodes in accordance with the changes to the stimulation parametersto steer the electrical stimulation around the short axis of themicrostimulator.
 16. The method of claim 15, wherein the redirectedelectrical stimulation stimulates substantially the same position alongthe cavernous nerve.
 17. The method of claim 14, further comprisingidentifying reduced stimulation of the cavernous nerve by sensingarterial pressure in the penis.
 18. The method of claim 14, furthercomprising identifying reduced stimulation of the cavernous nerve bysensing tumescence in the penis.
 19. The method of claim 1, wherein theat least two cathodic electrodes and one anodic electrode are leadless.